Alzheimer's disease (AD) is characterized by a dominant component of inflammation, which in concert with enhanced amyloid production leads to secondary neuronal degeneration. More recent evidence also suggests a strong link between cerebrovascular disease and development of dementia in AD. In recent studies, we have investigated the functions of prostaglandin receptor signaling pathways in a range of models of neurodegeneration. Prostaglandins are the downstream products of cyclooxygenase 1 and 2 activity (COX-1 and COX-2), and are lipid signaling molecules that bind a select class of G-protein coupled receptors. In our recent studies, we have determined that different prostaglandin receptors have pro- or anti- inflammatory effects in models of neuroinflammation as well as protective or toxic effects in models of cerebral ischemia. The goal of the present proposal is to validate the PGE2 EP4 receptor as a therapeutic target in the prevention and/or treatment of AD. The G-protein coupled PGE2 EP4 receptor is positively coupled to cAMP production, and exhibits significant anti-inflammatory effects in a number of non-neuronal models of inflammation as well as in a model of brain innate immunity. In addition, the EP4 receptor mediates pro-survival effects in models of excitotoxicity and cerebral ischemia. Thus, the combined anti-inflammatory and neuroprotective effects of EP4 signaling in brain makes it a very attractive therapeutic target for models of AD, in which there are components of both inflammation and neurotoxicity. The goal of the present proposal is to validate this receptor genetically and pharmacologically in aging APPSwe-PS1deltaE9 mice. Successful target validation of the EP4 receptor will provide the rationale for future and expanded pre-clinical assessment of agonists of this receptor in AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is characterized by a dominant component of inflammation, which in concert with increased amyloid production leads to neuronal injury and loss. The goal of the present proposal is to validate the PGE?EP4 receptor as a therapeutic target in the prevention and/or treatment of AD. Successful target validation of the EP4 receptor will provide the rationale for future and expanded pre-clinical assessment of agonists of this receptor in AD.